Compositions of iodophenyl sulfonates for X-ray visualization of the gastrointestinal tract

ABSTRACT

Disclosed are contrast agents of the formula ##STR1## contained in aqueous compositions and methods for their use in diagnostic radiology of the gastrointestinal tract wherein ##STR2## Z=H, halo, C 1  -C 20  alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups; 
     R=C 1  -C 25  alkyl, cycloalkyl, aryl, or halo-lower-alkyl, optionally substituted with halo, fluoro-lower-alkyl, lower-alkoxy, hydroxy, carboxy or lower-alkoxy carbonyl, lower-alkenyl, lower-alkynyl, lower-alkylene, lower-alkoxy-carbonyloxy; 
     n=1-5; 
     y=0-4; and 
     w=1-4 
     in an aqueous pharmaceutically acceptable carrier.

This application is a division of application Ser. No. 08/040,823, filedon Mar. 31, 1993, now U.S. Pat. No. 5,318,769.

FIELD OF THE INVENTION

This invention relates to aqueous compositions containing the contrastagents iodophenyl esters and iodophenyl sulfonates, and methods fortheir use in diagnostic radiology of the gastrointestinal tract.

Reported Developments

Roentgenographic examination utilizing X-rays and computed tomography(hereinafter CT) scans of fractures and other conditions associated withthe skeletal system is routinely practiced without the use of contrastagents. X-ray visualization of organs containing soft tissue, such asthe gastrointestinal (hereinafter GI) tract, requires the use ofcontrast agents which attenuate X-ray radiation. D. P. Swanson et al in"Pharmaceuticals In Medical Imaging", 1990, MacMillan PublishingCompany, provides an excellent background in medical imaging utilizingcontrast agents and compositions therewith.

Roentgenographic examination of the GI tract are indicated forconditions of digestive disorders, changes in bowel habit, abdominalpain, GI bleeding and the like. Prior to radiological examination,administration of a radiopaque contrast medium is necessary to permitadequate delineation of the respective lumen or mucosal surface fromsurrounding soft tissues. Accordingly, a contrast medium is administeredorally to visualize the mouth, pharynx, esophagus, stomach, duodenum andproximal small intestine. The contrast medium is administered rectallyfor examination of the distal small intestine and the colon.

The most widely used contrast agent for the visualization of the GItract is barium sulfate administered as a suspension orally or rectallyas an enema. (See, for example, U.S. Pat. Nos.: 2,659,690; 2,680,089;3,216,900; 3,235,462; 4,038,379 and 4,120,946) Notwithstanding itsrelatively good contrast characteristics, negligible absorption from theGI tract following oral or rectal administration and speedy excretionfrom the body, barium sulfate has certain disadvantages. In the presenceof intestinal fluids it lacks homogeneity and poorly adheres to mucusmembranes which can result in poor X-ray images. In the colon, whenadministered as an enema, it flocculates and forms irregular clumps withfecal matter.

Iodinated organic compounds have also been used as GI contrast agentssince the iodine atom is an effective X-ray absorber. They have the mostversatility and are utilized in the widest variety of procedures. Theyare very absorptive of X-rays with which the iodine interacts andproduce a so-called photoelectric effect which is a large magnificationin contrast caused by the photons stopped in the iodine-containingmedium. The magnification of contrast exceeds the level that would beexpected from relative changes in density. Because of thismagnification, relatively low concentrations of the contrast agent canbe utilized. (For iodinated agents see, for example, U.S. Pat. Nos.:2,786,055; 3,795,698; 2,820,814; 3,360,436; 3,574,718, 3,733,397;4,735,795 and 5,047,228.)

The desiderata for an ideal GI contrast agent includes: goodtoxicological profile; the ability to fill the entire bowel/lumen andevenly coat the gut mucosa so that the presence of the bowel isdetectable when the lumen is not distended; and nonirritation to theintestinal mucosa; and passage through the GI tract without producingartifacts or stimulating vigorous intestinal peristalsis.

We have found that compounds having these and other desirablecharacteristics in the GI tract should preferably have the followingproperties for inclusion in a suitable pharmaceutically acceptablevehicle for oral or rectal administration:

a partition coefficient, i.e. the ratio of hydrophobicity tohydrophilicity of about 10 or higher;

a melting point of less than about 80° C.; and

a molecular weight of at least about 200.

We have found that certain compounds hereinafter described possess thesedesirable properties when used in aqueous oral and rectal formulationsfor examination of the GI tract utilizing X-rays and CT scans.

SUMMARY OF THE INVENTION

In accordance with the invention, there is provided an x-ray contrastcomposition comprising solid particles of a contrast agent preferablyhaving:

a partition coefficient of about 10 or higher, and preferably, fromabout 10² to about 10⁸ ;

a melting point of less than 80° C., and preferably less than 60° C.;and

a molecular weight of at least 200, and preferably from about 200 toabout 2,000; and

a pharmaceutically acceptable aqueous carrier therefor.

In accordance with the present invention, there is also provided anx-ray contrast composition comprising a liquid x-ray contrast agenthaving:

a partition coefficient of about 10 or higher, and preferably, fromabout 10² to about 10⁸ ;

a molecular weight of at least 200, and preferably from about 200 toabout 2,000; and

a pharmaceutically acceptable aqueous carrier therefor.

In accordance with the invention there is further provided a method forx-ray diagnostic imaging of the GI tract which comprises orally orrectally administering to the patient an effective contrast producingamount of one of the above-described x-ray contrast compostions.

The composition for radiological examination of the GI tract comprises acompound of the formula or a pharmaceutically acceptable salt thereof:##STR3## wherein ##STR4##

Z=H, halo, C₁ -C₂₀ alkyl, cycloalkyl, lower alkoxy, cyano, where thealkyl and cycloalkyl groups can be substituted with halogen orhalo-lower-alkyl groups;

R=C₁ -C₂₅ alkyl, cycloalkyl, aryl or halo-lower-alkyl, optionallysubstituted with halo, fluoro-lower-alkyl, lower-alkoxy, hydroxy,carboxy or lower-alkoxy carbonyl, lower-alkenyl, lower-alkynyl,lower-alkylene or lower-alkoxy-carbonyloxy,

n is 1-5;

y is 0-4; and

w is 1-4.

As used herein, the term halogen (or halo) means fluorine, chlorine,bromine or iodine.

As used herein, the term cycloalkyl means carbocyclic rings having fromthree to eight ring carbon atoms including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cyclooctyl which may be substituted on anyring carbon atom thereof by one or more lower-alkyl groups, lower-alkoxygroups or halogens.

As used herein the terms lower-alkyl and lower-alkoxy mean monovalentaliphatic radicals, including branched chain radicals, of from one toten carbon atoms. Thus, the lower-alkyl moiety of such groups include,for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl,neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 2-hexyl, 3-hexyl, 1,1,3,3-tetramethylpentyl,1,1-dimethyloctyl and the like.

As used herein, the term lower-alkenyl and lower-alkynyl meansmonovalent, unsaturated radicals including branched chain radicals offrom three to ten carbon atoms and thus include 1-ethenyl,1-(2-propenyl), 1-(2-butenyl), 1-(1-methyl-2-propenyl),1-(4-methyl-2-pentenyl), 4,4,6-trimethyl-2-heptenyl, 1-ethynyl,1-(2-propynyl), 1-(2-butynyl), 1-(1 -methyl-2-propynyl),1-(4-methyl-2-pentynyl) and the like.

As used herein, the term alkylene means divalent saturated radicals,including branched chain radicals of from two to ten carbon atoms havingtheir free valences on different carbon atoms and thus includes1,2-ethylene, 1,3-propylene, 1,4-butylene, 1-methyl-1, 2-ethylene,1,8-octylene and the like.

As used herein, the term aryl means an aromatic hydrocarbon radicalhaving six to ten carbon atoms. The preferred aryl groups are phenyl,substituted phenyl and naphthyl substituted by from one to three, thesame or different members of the group consisting of lower-alkyl,halogen, hydroxy-lower-alkyl, alkoxy-lower-alkyl or hydroxy.

The x-ray contrast compound can comprise one, two, three or more iodineatoms per molecule; preferred species contain at least two, and morepreferably, at least three iodine atoms per molecule.

The solid x-ray contrast agents in particulate forms useful in thepractice of the present invention can be prepared by techniques known inthe art. The solid agents are comminuted to the desired size usingconventional milling methods, such as airjet or fragmentation milling.We have found that an effective average particle size of less than about100μ provides for good distribution and coating in the GI tract. As usedherein, particle size refers to a number average particle size asmeasured by conventional techniques, such as sedimentation field flowfractionation and disk centrifugation. An effective average particlesize of less than about 100μ means that at least about 90% of theparticles have a weight average particle size of less than about 100μ asmeasured by art recognized techniques.

A method for diagnostic imaging of the GI tract for use in medicalprocedures in accordance with this invention comprises orally orrectally administering to the mammalian patient in need of x-rayexamination, an effective contrast producing amount of a composition ofthe present invention. After administration, at least a portion of theGI tract containing the administered composition is exposed to x-rays toproduce an x-ray image pattern corresponding to the presence of thecontrast agent, then the x-ray image is visualized and interpreted usingtechniques known in the art.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the present invention can be made according to theschematic procedures shown or other methods using commercially availablestarting materials, intermediates and reagents. Starting materials,reagents and solvents can be obtained from chemical suppliers such asAldrich, Baker and Eastman Chemical Companies, or they may be preparedby techniques in the art. ##STR5## wherein Z, R, n and y are aspreviously described.

The following examples will further illustrate the compounds used in thepresent invention.

EXAMPLE 1 2,4,6-Triiodophenyl 2-ethylhexanoate ##STR6##

A solution of 2,4,6-triiodophenol (20.0 g, 42 mmol), 2-ethylhexanoylchloride (25 ml, 144 mmol, 3.5 eq.) and 4-dimethylaminopyridine (DMAP; 2mmol, 250 mg, 0.05 eq.) in 150 ml of pyridine was stirred overnite atroom temperature. The solution was poured into 1000 ml of 1N aqueoushydrochloric acid and the aqueous solution was extracted twice withethyl acetate. The combined organic layers were washed with aqueoushydrochloric acid, water, saturated aqueous sodium chloride and thendried over magnesium sulfate. The ethyl acetate solution was thenconcentrated under vacuum to give an oil (30 g) which was purified bysilica gel chromatography (5% ethyl acetate/hexanes eluent) to give theproduct. Concentration under high vacuum afforded 21 g (79%) of thedesired hexanoate ester as an oil. The product was taken up in hexanesand filtered through a pad of basic alumina. The filtrate wasconcentrated under high vacuum to give 16.9 g of analytically pureproduct.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₁₇ I₃ O₂ : C,28.12; H, 2.87; I, 63.66. Found: C, 28.27; H, 2.79; I, 63.62.

EXAMPLE 2 2.4,6-Triiodophenyl 2-methylpentanoate ##STR7##

Using the procedure described for the synthesis of 2,4,6-triiodophenyl(2-ethyl)hexanoate, 2,4,6-triiodophenyl 2-methylpentanoate was preparedin 25% yield as a solid, mp. 66°-68° C., from 2,4,6-triiodophenol (15.0g, 31.8 mmol), 2-methylvaleryl chloride (4.6 g, 34.2 mmol, 1.07 eq.) anda catalytic amount (0.1 g) of 4-dimethylaminopyridine in dry pyridine(20 ml).

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₂ H₁₃ I₃ O₂ :25.29; H, 2.30; I, 66.80. Found: C, 25.36; H, 2.13; I, 66.57.

EXAMPLE 3 2.4.6-Triiodophenyl 3-cyclopentyl propionate ##STR8##

A solution of 2,4,6-triiodophenol (15.0 g, 31.8 mmol),3-cyclopentylpropionyl chloride (14.6 ml, 95.4 mmol, 3 eq), pyridine(2.83 ml, 35.0 mmol, 1.1 eq) and 4-dimethylaminopyridine (200 mg) in 150ml of acetonitrile was heated to reflux under argon for 21 hrs and thencooled. The reaction solution was washed with water, saturated aqueoussodium chloride and then dried over magnesium sulfate. The organic layerwas filtered and concentrated under vacuum. The resulting residue waspurified by silica gel chromatography (1% ethyl acetate/hexanes) to give19.17 g of solid product. The solid was recrystallized from hexanes togive the final product as a feathery white solid.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₁₅ I₃ O₂ : C,28.21; H, 2.54; I, 63.88. Found: C, 28.25; H, 2.44; I, 64.06.

EXAMPLE 4 2,4,6-Triiodophenyl (2-propyl)pentanoate ##STR9##

A mixture of 2,4,6-triiodophenol (2.0 g, 4.24 mmol), 2-propylvaleroylchloride (2.5 ml, 12.7 mmol, 3 eq) and 4-dimethylaminopyridine (DMAP; 20mg) in 20 ml of acetonitrile was refluxed under argon overnite. Thereaction mixture was cooled and poured into excess aqueous sodiumbicarbonate and then extracted with dichloromethane. The dichloromethaneextract was dried over magnesium sulfate, filtered, and evaporated togive the crude product (2.42 mmol, 95%) as a pink solid.Recrystallization from ethyl acetate gave 1.75 g (68%) of pure product,mp 99°-101° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₁₇ I₃ O₂ : C,28.12; H, 2.87; I, 63.66. Found: C, 28.35; H, 2.80; I, 63.74.

EXAMPLE 5 2,4,6-Triiodophenyl perfluoroheptanoate ##STR10##

A mixture of 2,4,6-triiodophenol (2.0 g, 4.24 mmol), perfluoroheptanoicanhydride (10.3 g, 12.7 mmol, 3 eq) and 4-dimethylaminopyridine (DMAP;20 mg) in 20 ml of acetonitrile was heated to reflux under argon for 5hrs. On cooling, the resulting solution separated into two layerswhereupon the lower layer solidified. The solids were collected and thefiltrate was poured into excess saturated aqueous sodium bicarbonate.The aqueous mixture was extracted with dichloromethane; the organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo to give an off-white solid. The solid was recrystallized frommethanol to give the desired product (0.51 g, 14%) as white needles, mp71°-73° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₄ H₂ F₁₅ I₃ O₂ :C, 19.38; H, 0.23; I, 43.87. Found: C, 19.16; H, 0.02; I, 43.78.

EXAMPLE 6 2,4,6-triiodophenyl-tris-(2-ethylhexanoate) ##STR11##

The method of F. L. Weitle, J. Org. Chem. 41, 2044-2045 (1976) was usedto prepare 2,4,6-triiodophloroglucinol.

A mixture of 10.00 g (19.8 mmol) of 2,4,6-triiodophloroglucinol, 17.1 g(118.8 mmol) of 2-ethylhexanoic acid, 149.7 g (712.8 mmol) oftrifluoroacetic anhydride and 50 ml of anhydrous toluene was refluxedfor 18 hrs. The dark red solution was concentrated in vacuo to produce abrown oil. The oil was partitioned between 250 ml of ethyl acetate and100 ml of 5% potassium carbonate solution and the ethyl acetate layerwas washed with saturated sodium bicarbonate solution (100 ml), brine(50 ml) and dried over sodium sulfate. Concentration in vacuo produced abrown oil. The oil was purified by flash chromatography on 713 g ofsilica gel with 5% ethyl acetate/hexane as the eluent. Concentration invacuo produced 16.25 g (93%) of product as a yellow oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: (M+1)⁺ 883.

EXAMPLE 7 2,4,6-Triiodophenyl dodecanoate ##STR12##

Dodecanoyl chloride (2.95 ml, 12.8 mmol) was added to a suspension of2,4,6-triiodophenol (6.0 g, 12.7 mmol) in refluxing acetonitrile (50 ml)and the mixture was heated under argon for 24 hrs. The reaction mixturewas cooled and washed with saturated aqueous sodium bicarbonate. Theorganic layer was dried over magnesium sulfate, filtered, and evaporatedto dryness under vacuum to give an off-white solid. The crude productwas recrystallized from methanol to give 6.9 g (83%) of the desiredester, mp 68°-69° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. Calculated for C₁₈ H₂₅ I₃ O₂ : C,33.05; H, 3.85; I, 58.20. Found: C, 32.91; H, 3.75; I, 58.25.

EXAMPLE 8 3-Trifluoromethyl-2,4,6-triiodophenyl 2-ethyl hexanoate##STR13##

A mixture of 9.00 g (55.5 mmol) of α,α,α,-trifluoro-m-cresol, 31.4 g(374 mmol) of NaHCO₃ and 59.9 g (172 mmol) of benzyltrimethylammoniumdichloroiodate in 78 ml dichloromethane/30 ml methanol was placed undernitrogen and stirred for 22 hrs. The mixture was filtered and the NaHCO₃was washed with 200 ml of dichloromethane. The filtrate was washed with1M HCl (150 ml) 5% NaHSO₃ (100 ml) and brine (100 ml). The solution wasdried over Na₂ SO₄ and concentrated in vacuo to 27.1 g of brown solid.The solid was dissolved in a minimum amount of dichloromethane and waspurified by flash chromatography on 678 g of silica gel with 30%dichloromethane/hexane as the eluent to afford 13.55 g (45%) of3-trifluoromethyl-2,4,6-triiodophenyl 2-ethyl hexanoate as a pink solid.¹ H-NMR (300 MHz) spectral data were consistent with the desiredstructure.

A mixture of 10.0 g (18.53 mmol) of 2,4,6-triiodo-3-trifluoromethylphenol, 3.62 g (22.2 mmol) of 2-ethylhexanoyl chloride and 0.226 g (1.85mmol) of 4-dimethylaminopyridine in 37 ml of dry dichloromethane wasplaced under nitrogen and cooled to 0° C. Triethylamine (2.25 g, 22.2mmol) was added dropwise and the resulting solution was stirred for 16hrs at room temperature. The mixture was partitioned between 200 ml ofdichloromethane and 100 ml of 1M HCl. The dichloromethane layer waswashed with saturated NaHCO₃ solution (50 ml) and brine (100 ml). Thesolution was dried over Na₂ SO₄ and concentrated in vacuo to 12.80 g ofbrown oil. The oil was purified by flash chromatography on 20 g ofsilica gel with 3% ethyl acetate/hexane as the eluent. Concentration invacuo afforded 11.63 g (94%) of product as a light yellow oil.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: M⁺ 666. Calculated forC₁₅ H₁₆ F₃ I₃ O₂ : C, 27.05; H, 2.42; I 57.16. Found: C, 27.47; H, 2.42;I, 56.88.

EXAMPLE 9 2,4,6-triiodophenyl-bis-(2-methylpentanoate) ##STR14##

A mixture of 1.00 g (9.08 mmol) of resorcinol, 6.12 g (61.1 mmol) ofcalcium carbonate and 9.80 g (28.2 mmol) of benzyltrimethylammoniumdichloroiodate (BTMAICl₂) in 13 ml dichloromethane/5 ml methanol wasplaced under nitrogen and stirred for 4 hrs. The mixture was filteredand concentrated in vacuo. The resulting residue was partitioned between100 ml of ethyl acetate and 50 ml of saturated NaHCO₃ solution. Theethyl acetate layer was washed with brine (25 ml) and dried over Na₂SO₄. Concentration in vacuo produced a dark brown solid. The solid wasdissolved in a minimum amount of ethyl acetate and was purified by flashchromatography on 100 g of silica gel with 20% ethyl acetate/hexane asthe eluent. The first 125 ml to elute contained nothing while the pureproduct eluted with the next 224 ml. Concentration in vacuo afforded2.78 g (63%) of 2,4,6-triiodoresorcinol as a cream colored solid. ¹H-NMR (300 MHz) spectral data were consistent with the desiredstructure.

A mixture of 0.500 g (1.03 mmol) of 2,4,6-triiodoresorcinol and 0.304 g(2.26 mmol) of 2-methylpentanoyl chloride in 2 ml of dry dichloromethanewas placed under nitrogen. A solution containing 0.207 g (2.05 mmol) oftriethylamine and 0.125 g (1.03 mmol) dimethylaminopyridine in 2 ml ofdry dichloromethane was added dropwise while stirring. After completeaddition the resulting light brown solution was stirred 30 min undernitrogen. The solution was partitioned between 50 ml of dichloromethaneand 50 ml of 1M HCl. The dichloromethane layer was washed with saturatedNaHCO₃ solution (50 ml) and brine (25 ml). The solution was dried overNa₂ SO₄ and concentrated in vacuo to 0.677 g of brown oil. The oil waspurified by flash chromatography on 20 g of silica gel with 5% ethylacetate/hexane as the eluent. Concentration in vacuo afforded 0.622 g(88%) of product as a colorless oil which slowly solidified over sevendays.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. FAB/MS: (M+1)⁺ 685. Calculatedfor C₁₈ H₂₃ I₃ O₄ : C, 31.60; H, 3.39. Found: C, 31.79; H, 3.32, mp44.5°-47.0° C.

EXAMPLE 10 2,4,6-Triiodophenyl hexanesulfonate ##STR15##

A solution of 10 g (0.021 mol) of 2,4,6-triiodophenol in 250 ml ofmethylene dichloride was stirred in an ice bath with 12.6 ml oftriethylamine. To this solution was added dropwise 8.5 g (0.046 mol) ofhexanesulfonyl chloride in 50 ml of methylene chloride. The reactionmixture was then stirred for 18 hrs at room temperature. Water was addedand after separation, the organic layer was washed with saturatedpotassium carbonate and brine. The solution was dried over MgSO₄,filtered and concentrated to afford 13.5 g of crude product.Chromatography on 250 g of silica gel using 10% ethyl acetate/hexaneafforded 9.8 g of product which upon recrystallization twice from hexanegave 6.5 g (50%) of 2,4,6-triiodophenyl hexanesulfonate, mp 70°-71° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. MS; MH⁺ 621, M⁺ 620. Calculatedfor C₁₂ H₁₅ O₃ SI₃ : C, 23.47; H, 2.44; S, 5.17; I, 61.40. Found: C,23.26; H, 2.31; S, 5.21; I, 61.32.

EXAMPLE 11 2,4,6-Triiodophenyl heptanesulfonate ##STR16##

Using the same procedure as for 2,4,6-triiodophenyl hexanesulfonate,2,4,6-triiodophenyl heptanesulfonate was prepared from 15 g (0.032 mol)of 2,4,6-triiodophenol in 33% yield, mp 78°-80° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. MS; MH⁺ 635. Calculated for C₁₃H₁₇ O₃ SI₃ : C, 24.63; H, 2.70; S, 5.06; I, 60.04. Found: C, 24.71; H,2.59; S, 5.06; I, 59.96.

EXAMPLE 12 2,4,6-Triiodophenyl decanesulfonate ##STR17##

Using the same procedure as for 2,4,6-triiodophenyl hexanesulfonatewithout the chromatography step, 2,4,6-triiodophenyl decanesulfonate wasprepared from 10 g (0.021 mol) of 2,4,6-triiodophenol in 59% yield, mp71°-72° C.

Title Compound: ¹ H (300 MHz) and ¹³ C (75 MHz) NMR spectra wereconsistent with the desired structure. MS; MH⁺ 677. Calculated for C₁₆H₂₃ O₃ SI₃ : C, 28.42; H, 3.43; I, 4.71; S, 56.31. Found: C, 28.47; H,3.28; I, 4.73; S, 56.53.

Compositions of the Present Invention

The contrast agents are formulated for administration usingphysiologically acceptable carriers or excipients in a manner within theskill of the art. The compounds with the addition of pharmaceuticallyacceptable aids (such as surfactants and emulsifiers) and excipients maybe suspended or partially dissolved in an aqueous medium resulting in adispersion, solution or suspension. However, the oily contrast agentsare preferably made into emulsions.

Compositions of the present invention comprise the followingpharmaceutically acceptable components based on % w/v:

Non-aqueous phase 1-50

Contrast Agent 0.001-75

Excipient 0-20

Aids/Surfactants/Emulsifiers) 0.01-15

Water q.s. to 100

Specific Examples of the compositions of the present invention are shownin Examples 13-15.

EXAMPLE 13

2,4,6-Triiodophenyl 2-ethylhexanoate 23.7 % (w/v)

Safflower Oil 20.0% (w/v)

Tween 21 2.5 % (w/v)

Hydroxypropylmethylcellulose (4000 cPs) 0.5% (w/v)

q.s. with water to 100% volume and shake

EXAMPLE 14

2,4,6-Triiodophenyl 2-methylpentanoate 55.3 % (w/v)

Dow Corning Medical Antifoam AF 40.0 % (w/v)

q.s. with water to 100% volume and shake

EXAMPLE 15

2,4,6-Triiodophenyl 3-cyclopentyl propionate 25.9 % (w/v)

Simplesse® Dietary Fat Substitute 30.0% (w/v)

Hydroxypropylmethylcellulose (4000 cPs) 0.5 % (w/v)

q.s. with water to 100% volume and shake

The nonaqueous phase comprises vegetable oils such as safflower oil;non-metabolizing fat substituents, such as Simplesse; fluorinatedhydrocarbons, such as perfluorodecalin; mineral oil and simethicone.

Excipients advantageously used in the formulations include viscositymediating and stabilizing agents, such as microcrystalline cellulose,ethylcellulose, hydroxypropyl methylcellulose and gum arabic.Physiologically acceptable substances may also be included, such assodium citrate, sodium chloride, therapeutic substances, antacidsubstances and flavoring agents. The inclusion ofantimicrobial/antiseptic agents such as methyl parahydroxybenzoate,ethyl para-hydroxybenzoate, propyl parahydroxybenzoate, benzoic acid orsorbic acid may also be desirable in some formulations.

As known by those skilled in the art, surfactants or emulsifiers canreduce the interfacial tension between two immiscible phases, i.e.,oil-in-aqueous medium. These agents can be used alone or in combinationwith other emulsifying agents and surfactants. For example, Dow CorningMedical Antifoam AF, which is a composition of 30% w/vpolydimethylsiloxane (simethicone) and silica aerogel, 14% w/v stearateemulsifiers and 0.075% w/v sorbic acid, the balance being water, may beused by itself. Intralipid, which is an emulsion of fatty acids needsthe presence of a suspending agent for it to form an acceptable emulsionwith contrast agents of the present invention. The amount of suchsurfactants may be in the range of from 0.01 to 15% w/v of the aqueousformulations, although the amount, in general, is kept as low aspossible, preferably in the range of 0.05 to 5% w/v. The surface activeagents may be cationic, anionic, nonionic, zwitterionic or a mixture oftwo or more of these agents.

Suitable cationic surfactants include cetyl trimethyl ammonium bromide.Suitable anionic agents include sodium lauryl sulphate, sodiumheptadecyl sulphate, alkyl benzenesulphonic acids and salts thereof,sodium butylnapthalene sulfonate, and sulphosuccinates. Zwitterionicsurface active agents are substances that when dissolved in water theybehave as diprotic acids and, as they ionize, they behave both as a weakbase and a weak acid. Since the two charges on the molecule balance eachother out the molecules act as neutral molecules. The pH at which thezwitterion concentration is maximum is known as the isoelectric point.Compounds, such as certain amino acids having an isoelectric point atthe desired pH of the formulations of the present invention are usefulin practicing the present invention.

In preparing the formulations of the present invention we prefer to usenonionic emulsifiers or surface active agents which, similarly to thenonionic contrast agents, possess a superior toxicological profile tothat of anionic, cationic or zwitterionic agents. In the nonionicemulsifying agents the proportions of hydrophilic and hydrophobic groupsare about evenly balanced. They differ from anionic and cationicsurfactants by the absence of charge on the molecule and, for thatreason, are generally less of an irritant than the cationic or anionicsurfactants. Nonionic surfactants include carboxylic esters, carboxylicamides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols.

One particular type of carboxylic ester nonionic surface active agentsare the partial, for example mono-, esters formed by the reaction offatty and resin acids, for example of about 8 to about 18 carbon atoms,with polyhydric alcohols, for example glycerol, glycols such as mono-,di-, tetra- and hexaethylene glycol, sorbitan, and the like; and similarcompounds formed by the direct addition of varying molar ratios ofethylene oxide to the hydroxy group of fatty acids.

Another type of carboxylic esters is the condensation products of fattyand resin partial acids, for example mono-, esters ethylene oxide, suchas fatty or resin acid esters of polyoxyethylene sorbitan and sorbitol,for example polyoxyethylene sorbitan, monotall oil esters. These maycontain, for example, from about 3 to about 80 oxyethylene units permolecule and fatty or resin acid groups of from about 8 to about 18carbon atoms. Examples of naturally occurring fatty acid mixtures whichmay be used are those from coconut oil and tallow while examples ofsingle fatty acids are dodecanoic acid and oleic acid.

Carboxylic amide nonionic surface active agents are the ammonia,monoethylamine and diethylamine amides of fatty acids having an acylchain of from about 8 to about 18 carbon atoms.

The ethoxylated alkylphenol nonionic surface active agents includevarious polyethylene oxide condensates of alkylphenols, especially thecondensation products of monoalkylphenols or dialkylphenols wherein thealkyl group contains about 6 to about 12 carbon atoms in either branchedchain or particularly straight chain configuration, for example, octylcresol, octyl phenol or nonyl phenol, with ethylene oxide, said ethyleneoxide being present in amounts equal to from about 5 to about 25 molesof ethylene oxide per mole of alkylphenol.

Ethoxylated aliphatic alcohol nonionic surface active agents include thecondensation products of aliphatic alcohols having from about 8 to 18carbon atoms in either straight chain or branched chain configuration,for example oleyl or cetyl alcohol, with ethylene oxide, said ethyleneoxide being present in equal amounts from about 30 to about 60 moles ofethylene oxide per mole of alcohol.

Preferred nonionic surface active agents include: sorbitan esters (soldunder the trade name Span) having the formula: ##STR18## wherein R₁ =R₂=OH, R₃ =R for sorbitan monoesters,

R₁ =OH, R₂ =R₃ =R for sorbitan diesters,

R₁ =R₂ =R₃ =R for sorbitan triesters,

where R=(C₁₁ H₂₃) COO for laurate,

(C₁₇ H₃₃) COO for oleate,

(C₁₅ H₃₁) COO for palmitate,

(C₁₇ H₃₅) COO for stearate.

Polyoxyethylene alkyl ethers (i.e. Brijs) having the formula:

    CH.sub.3 (CH.sub.2).sub.x (O--CH.sub.2 --CH.sub.2).sub.y OH

where (x+1) is the number of carbon atoms in the alkyl chain, typically:

12 lauryl (dodecyl)

14 myristyl (tetradecyl)

16 cetyl (hexadecyl)

18 stearyl (octadecyl)

and y is the number of ethylene oxide groups in the hydrophilic chain,typically 10-60.

Polyethylene sorbitan fatty acid esters, sold under the trade names ofPolysorbates 20, 40, 60, 65, 80 & 85.

Polyethylene stearates, such as:

poly(oxy-1,2-ethanediyl),α-hydro-ω-hydroxyoctadecanoate;

polyethylene glycol monostearate; and

poly(oxy-1,2-ethanediyl)-α-(1-oxooctadecyl)-ω-hydroxy-

polyethylene glycol monostearate

The dosages of the contrast agent used according to the method of thepresent invention will vary according to the precise nature of thecontrast agent used. Preferably, however, the dosage should be kept aslow as is consistent with achieving contrast enhanced imaging. Byemploying as small amount of contrast agent as possible, toxicitypotential is minimized. For most contrast agents of the presentinvention dosages will be in the range of from about 0.1 to about 16.0 giodine/kg body weight, preferably in the range of from about 0.5 toabout 6.0 g iodine/kg of body weight, and most preferably, in the rangeof from about 1.2 to about 2.0 g iodine/kg body weight for regular X-rayvisualization of the GI tract. For CT scanning, the contrast agents ofthe present invention will be in the range of from about 1 to about 600mg iodine/kg body weight, preferably in the range of from about 20 toabout 200 mg iodine/kg body weight, and most preferably in the range offrom about 40 to about 80 mg iodine/kg body weight.

The concentration of the contrast agent should be in the range of fromabout 0.001% w/v to about 75% w/v of the formulation, preferably fromabout 0.05% w/v to about 50% w/v and most preferably of from about 0.1%w/v to about 20% w/v.

The invention having been fully described, it will be apparent to oneskilled in the art that changes and modifications can be made theretowithout departing from the spirit and scope thereof.

What is claimed is:
 1. A compound of the formula or a pharmaceutically acceptable salt thereof: ##STR19## wherein X=--SO₂ --;Z=H, halo, C₁ -C₂₀ alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl group; can be substituted with halogen or halo-lower-alkyl groups; R=C₁ -C₂₅ alkyl, cycloalkyl, aryl or halo-lower-alkyl, each of which may be optionally substituted with halo, fluoro-lower-alkyl, lower-alkoxy, hydroxy, carboxy or lower-alkoxy carbonyl, lower-alkenyl, lower-alkynyl, lower-alkylene or lower-alkoxycarbonyloxy; n=1-5; y=0-4; and w=1-4;with the proviso that when n=1, Z=H or OCH₃, and w=1, R cannot be CF₃, C₂ H₄ Cl, or a phenyl group substituted by CH₃, OCH₃, F, or CO₂ CH₃.
 2. A compound according to claim 1, selected from the group consisting of: 2,4,6-triiodophenyl hexanesulfonate, 2,4,6-triiodophenyl heptanesulfonate, and 2,4,6-triiodophenyl decanesulfonate.
 3. An orally or rectally administerable x-ray contrast composition for visualization of the gastrointestinal tract comprising a contrast agent having the formula, or a pharmaceutically acceptable salt thereof: ##STR20## wherein ##STR21## Z=H, halo, C₁ -C₂₀ alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;R=C₁ -C₂₅ alkyl, cycloalkyl, aryl or halo-lower-alkyl, each of which may be optionally substituted with halo, fluoro-lower-alkyl, lower-alkoxy, hydroxy, carboxy or lower-alkoxy carbonyl; lower-alkenyl, lower-alkynyl, lower-alkylene or lower-alkoxy-carbonyloxy; n=1-5; y=0-4; and w=1-4 in an aqueous pharmaceutically acceptable carrier.
 4. The x-ray contrast composition of claim 3 wherein said contrast agent is selected from the group consisting of: 2,4,6-triiodophenyl hexanesulfonate, 2,4,6-triiodophenyl heptanesulfonate, and 2,4,6-triiodophenyl decanesulfonate.
 5. The x-ray contrast composition of claim 3 containing at least one surfactant.
 6. The x-ray contrast composition of claim 5 wherein said surfactant is cationic.
 7. The x-ray contrast composition of claim 5 wherein said surfactant is anionic.
 8. The x-ray contrast composition of claim 5 wherein said surfactant is zwitterionic.
 9. The x-ray contrast composition of claim 5 wherein said surfactant is nonionic.
 10. The x-ray contrast composition of claim 6 wherein said cationic surfactant is cetyl trimethyl ammonium bromide.
 11. The x-ray contrast composition of claim 7 wherein said anionic surfactant is selected from the group consisting of sodium lauryl sulfate, sodium heptadecyl sulphate, an alkyl benzenesulphonic acid, sodium butylnaphthalene sulfonate and sulphosuccinate.
 12. The x-ray contrast composition of claim 9 wherein said nonionic surfactant is selected from the group consisting of carboxylic esters, carboxylic amides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols, sorbitan esters, polyoxyethylene alkyl ethers and polyoxyethylene sorbitan fatty acid esters.
 13. A method of carrying out x-ray examination of the gastrointestinal tract of a patient in need of such examination which comprises orally or rectally administering to the patient an x-ray contrast composition comprising:an x-ray contrast agent, or a pharmaceutically acceptable salt thereof, having the formula: ##STR22## wherein ##STR23## Z=H, halo, C₁ -C₂₀ alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups; R=C₁ -C₂₅ alkyl, cycloalkyl, aryl or halo-lower-alkyl, each of which may be optionally substituted with halo, fluoro-lower-alkyl, lower-alkoxy, hydroxy, carboxy or lower-alkoxy carbonyl; lower-alkenyl, lower-alkynyl, lower-alkylene or lower-alkoxy-carbonyloxy; n=1-5; y=0-4; and w=1-4 in an aqueous pharmaceutically acceptable carrier.
 14. The method of claim 13 wherein said contrast agent is selected from the group consisting of: 2,4,6-triiodophenyl hexanesulfonate, 2,4,6-triiodophenyl heptanesulfonate, and 2,4,6-triiodophenyl decanesulfonate.
 15. The method of claim 13 wherein the amount of contrast agent administered to said patient contains from about 0.1 to about 16 g iodine/kg body weight for regular x-ray visualization of the gastrointestinal tract.
 16. The method of claim 13 wherein the amount of contrast agent administered to said patient contains from about 1 to about 600 mg iodine/kg body weight for CT scan visualization of the gastrointestinal tract.
 17. The method of claim 13 wherein said contrast agent is present in said x-ray contrast composition in the form of a dispersion.
 18. The method of claim 17 wherein said contrast agent is in the form of an emulsion.
 19. The method of claim 17 wherein said dispersion contains at least one surfactant.
 20. The method of claim 19 wherein said surfactant is cationic.
 21. The method of claim 19 wherein said surfactant is anionic.
 22. The method of claim 19 wherein said surfactant is zwitterionic.
 23. The method of claim 19 wherein said surfactant is nonionic.
 24. The method of claim 20 wherein said cationic surfactant is cetyl trimethylammonium bromide.
 25. The method of claim 21 wherein said anionic surfactant is selected from the group consisting of sodium lauryl sulfate; sodium heptadecyl sulphate, an alkyl benzenesulphonic acid, sodium butylnaphthalene sulfonate and sulphosuccinates.
 26. The method of claim 23 wherein said nonionic surface active agent is selected from the group consisting of carboxylic esters, carboxylic amides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols, sorbitan esters, polyoxyethylene alkyl ethers and polyoxyethylene sorbitan fatty acid esters. 